Salivary gland dysfunction occurs as a result of pathological injury after radiotherapy for head and neck cancer and significantly compromises the oral health and quality of life of patients. Salivary function and regeneration, as well as the maintenance of epithelial progenitor cells, is dependent on parasympathetic innervation: regeneration only occurs if parasympathetic input is maintained. Current efforts to regenerate salivary tissue and restore function do not address the need to repair parasympathetic innervation. Therefore, in this application we propose to restore salivary function by re-establishing the nerve supply through the use of Schwann cells. Schwann cells are essential for neuronal function, survival and regeneration, and maintaining tissue innervation. We hypothesize that maintaining Schwann cells after radiation, or transplanting autologous Schwann cells into radiation-damaged salivary glands, will enhance neuronal input and promote tissue regeneration. Thus, the Specific Aims of this project are to: 1) Determine the impact of gamma radiation on Schwann cell-neuronal cell interactions; 2) Identify the effects of Neuregulin-1 produced by the nerves on Schwann cell and neuronal survival, nerve function, and epithelial regeneration after irradiation; and 3) Determine the ability of Schwann cells to restore salivary function after irradiation. These aims will be achieved using embryonic ex vivo and adult mouse in vivo models of irradiation in the submandibular gland in conjunction with genetic, biochemical, immunochemical, and fluorescence imaging techniques. Importantly, biopsies from irradiated human glands will be analyzed in parallel. Our investigation will provide sufficient proof-of-principle to support the development of this regenerative strategy in human studies and facillitate our understanding of how radiation influences salivary gland regeneration and repair. PUBLIC HEALTH RELEVANCE Salivary glands are irreversibly damaged after treatment with radiotherapy for head and neck cancer, and this substantially reduces oral health and quality of life. This project employs embryonic and adult mouse models of radiation-induced salivary gland injury to develop a method using the nerve support cells, called Schwann cells, to re-establish a functional nerve supply essential for gland repair, regeneration and secretion. Our goal is to develop this approach into a regenerative treatment for the restoration of salivary function in human patients.